4-pregneno-[3, 2-c] pyrazoles and processes of preparing them



ited States Patent 'Office Patented Jan. 17, 1967 3,299,054 4-PREGNENO-[3,2-c]PYRAZLlES AND PROCESSES F PREPARENG THEM Max Tishler, Westfield, N.J., Nathan G. Steinherg, Brooklyn, N.Y., and Ralph F. Hirschmann, Scotch Plains,

NJL, assignors to Merck 81 Co., Inc., Rahway, N.J., a

corporation of New Jersey N0 Drawing. Original application Dec. 1, 1961, Ser. N0.

156,465, now Patent No, 3,067,193, dated Dec. 4, 1962.

Divided and this application July 2, 1962, Ser. No.

1 Claim. (Cl. 260239.5)

This invention is concerned generally with novel 4- pregneno-[3,2-c]pyrazole compounds, and with processes of preparing the same. More particularly, it relates to novel 2l-hydroxy-, 2l-acyloxy-, 21-desoxy-, and 21- fluoro 17cc hydroxy 20 oxo 4 pregneno [3,2 c] pyrazole compounds and to processes of making these compounds starting from the corresponding l7u,2ldihydroxy-4-pregnene-3,20dione.

This application is a division of co-pending application Serial No. 156,465, filed December 1,1961, now US. Patent No. 3,067,193, which application is, in turn, a continuation-in-part of application Serial No. 71,178, filed November 23, 1960, now abandoned.

These novel 4-pregneno-[3,2-c]pyrazole compounds, subject of the present invention, may be chemically represented by structures A and B:

wherein R is -halogen, 5-hydroxy or keto, but 5-halogen is present at R, only when X is halogen, R is a-fluoro, hydrogen or a-methyl, R is hydrogen, amethyl, 5-methyl, or methylene, R is hydrogen, hydroxy, acyloxy or fiuoro, R is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or acyl and X is hydrogen or halogen, but hydrogen is present at not more than three of the four postion R R R and X, and wherein any acyl group present as an acyloxy group at R, may be the same or different from any acyl group present at R N-substituted-pyrazole compounds having structure A are herein designated as the 1'-substituted-4-pregneno-[3,2-c]pyrazoles, and N-substltuted-pyrazole compounds having structure B are designated as the 2-substituted-4-pregnena-[3,2-c]pyrazoles.

The above defined 4-pregneno-[3,2-c1pyrazoles produced in accordance with the present invention possess high anti-inflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesirable side ellects.

In preparing our novel chemical compounds, the starting material utilized is a l70,2l-dihydr0Xy-4-pregnene- 3,20-dione which may be identified by the following structural formula:

wherein R is 5-hydroxy or 5-halogen, but 5-halogen is present at R only when X is halogen, R is hydrogen, a-flUOI-O or a-methyl, R is hydrogen, a-methyl, 5-methyl or methylene, and X is hydrogen or halogen, but hydrogen is present at not more than two of the three positions R R and X. However, it is clear to those skilled in the art that other starting materials may be similarly converted to the desired end products.

Among the compounds which may be used as a starting material in the process of our invention are:

l l5,17a,21-t1'ihydroxy-16a-methyl 4-pregnene-3 ,20-dione,

1 l5,17a,21-trihydroxy--methyl-4-pregnene-3 ,20-dione,

1 15, 17 (1,2 l-trihydroxy- 1 6-methylene-4-pregnene-3 ,20-

dione,

l 15, L,2 1-trihydroxy-6ot-methyl-4-pregnene-3 ,20-dione,

115,17a,21-trihydroxy-6a,l6a-din1ethyl-4-pregnene- 3 ,20-dione,

l l5,17a,2l-trihydroxy-6a,165-dimethyl-4-pregnene- 3 ,ZO-dione,

1 15,170,21-trihydroxy-6u-methyl-16-methylene-4- pregnene-3,20-dione,

6a-fiuoro-1 15,17u,21-trihydroxy-4-pregnene-3 ,20-dione,

oa-fluoro-l 15,1701,2l-trihydroxy-l6-methylene4- pregnene-3 ,ZO-dione,

9a-fluoro-115,17a,2l-trihydroXy-4-pregnene-3 ,ZO-dione,

9a-fluoro-115,170:,21-trihydroxy-16amethyl-4-pregnene 3 ,20-dione,

9a-flLI01'O-l 15, 170:,2 l-trihydroxy-l65-methyl-4- pregnene-3 ,20-dione,

9a-fiuoro-115,l7a,21-trihydroxy-16-methylene- 4-pregnene-3 ,ZO-dione,

9a-chloro-l 15, 17a,21-trihydroXy-4-pregnene-3,20dione,

9ei-chloro-l 15, 17a,21-tri'hydroxyl6a-methyl-4-pregnene- 3,20-dione,

9oc-Cl'1lO1'O-l 15,17a,21-trihydroxy-165-methyl-4-pregnene- 3 ,ZO-dione,

9 a-Cl'llOlO-l 15,17a,21-trihydroxy-16-rnethylene-4- pregnene3,2()'dione,

9u-fluoro-l15,17a,2l-trihydroxy-6a-methyl-4-pregnene- 3,20-dione,

9u-fiuoro-l1/3,l7a,21-trihydroxy-6a,16 3-dimethyl-4- pregnene-3,20-dione,

9a-fluoro-l 15,17a,21-trihydrxy-6a-methy1-l6- methylene-4-pregnene-3,ZO-dione,

9a-chloro-1 1 8,17a,21-trihydroxy-6a,16ot-dimethyl-4- pregnene-3,20-dione,

9u-chloro-l1B,17u,21-trihydroxy-6u,16fl-dimethyl-4- pregnene-3,20-dione,

9a-chloro-1lfi, l7a,2l-trihydroxy-6a-rnethyl-l6- methylene-4-pregnene-3,20-dione,

6a,9a-difluoro-l1B,17a,21-trihydroxy-4-pregnene-3 ,20-

dione,

6a,9a-difluoro-1 l5, l7a,21-trihydroxy-16wmethyl-4- pregnene-3,20-dione,

6a,9a-difiuoro-11B,17a,21-trihydr0xy-16/9-methyl- 4-pregnene-3,20-dione,

6a,9a-difiuoro-11/3,17a,2l-trihydroxy-l6-methylene- 4-pregnene-3 ,20-dione,

9ot-chloro-6a-fiuoro-l1 8,l7a,2l-trihydroxy-4-pregnene- 3,20-dione,

9oc-ChlO1'O-6a-fiUOIO-1 1B, 17 1,21-tri'hyd-roxy-16amethyl-4-pregnene-3,20-dione,

9a-chloro-6a-fluoro-l 1B, l7ot,21-trihydr0xy-16- methylene-4-pregnene-3,20-dione,

and the 1 l-keto-analogues of the above compounds;

9a,11fi-dichloro-l7a,2l-dihydroxy-4-pregnene-3,20-

dione,

90:,1 lB-dichloro-17a,2 l-dihydroxy-l 6a-methyl-4- pregnene-3,20-dione,

9a,1lfl-dichloro-17a,2l-dihydroxy-l65-methyl-4- pregnene-3,20-dione,

904,1 lfl-dichlor0-17a,2 l-dihydroxy-l6-methylene-4- pregnene-3,20-dione,

911,1lB-dichloro-6a-fiuoro-17a,2l-dihydroxy-4-pregnene- 3,20-dione,

9a,1 ifl-dichloro-6a-fluoro-17a,21-dihydroxy-16- methylene-4-pregnene-3,20-dione,

90:, l lB-dichloro-17a,2 l-dihydroxy-6a-methyl-4-pregnene- 3,20-dione,

9a, 1 lfi-dichloro-l7a,21-dihydroxy-6u, l6a-dimethyl- 4-pregnene-3,20-dione,

901,1lfl-dichloro-17a,21-dihydroxy-6a-methyl-l6- methylene-4-pregnene-3 ,ZO-dione,

9a-bromo-l lfl-chloro-l7a,2l-dihydroxy-4-pregnene- 3,20-dione,

9a-bromo-l 1/3chloro-17a,21-dihydroXy-16a-methyl- 4-pregnene-3,20-dione,

9u-bromo-l lB-chloro-l7a,2 l-dihydroxy-l6fi-methyl- 4-pregnene-3,20-dione,

9a-bromo-l1,8-chloro-17a,2l-dihydroxy-16-methylene- 4-pregnene-3,2()-dione,

9u-bromo-l 1,8-chloro-17a,21-dihydroxy-6a-fluorol6a-methyl-4-pregnene-3,20-dione,

9u-bromo-1 1 fi-chloro- 17 (1,2l-dihydroxy-6a-fiuoro-l 6,8-

methyl-4-pregnene-3,20-dione,

9a-bromo-l lfi-chlorol7a,2l-dihydroxy-6a-fluoro- 16-rnethylene-4-pregnene-3,20-dione,

9u-bromo-1 IB-chloro-17a,21-dihydroxy-6a methyl- 4-pregnene-3,20-dione,

9a-bromo-11B-chloro-17a,2l-dihydroxy-6a,l6a-

dimethyl-4-pre gnene-3 ,20-di one,

4 9a-bromo-1Iii-chloro-17a,2l-dihydroxy-6a,165-

dimethyl-4-pregnene-3,20-dione, 9a-bromo-l1fi-chloro-17a,2l-dihydroxy-Ga-methyl- 16-met'hylene-4-pregnene-3,20-dione and the like.

The above-named starting materials for our invention can be prepared by the introduction of the various substituents, namely the 16a-methyl-, l6,6-methyl-, 16-methylene-, 6a-methyl-, 6ot-flLlOI0-, 9a-fiuoro or the 9oc-Chl0f0 groups into a 17a,21-dihydroxy-4apregnene-3,ZO-dione according to known procedures capable of general application. More than one substituent may be introduced into the unsubstituted steroid in any order, although it is generally preferred to introduce a 9a-halogen substituent last.

An 11B,17a,21-trihydroxy-4pregnene-3,20-dione compound may be converted into the correspondingly substituted 9a,1l}3-diChl0IO-, or the 9a-bromo-11B-chloro-17a. 21-dihydroxy-4 pregnene-3,20-dione compound by first dehydrating the 11fl,17a,21-trihydroXy-4-pregnene-3,20- dione at the 9(11)-position to form the corresponding 9(11)-pregnene, then .actylating at the 21-position, and finally halogenating at the 9a,11B-positions, for example, following the detailed procedures given on page 68.

It has beenfound that the starting materials defined above will react with aqueous formaldehyde solutions in the presence of strong acid to form compounds having the formula:

wherein R is ,B-hydroxy 0r B-halogen but [fl-halogen is present at R; only when X is halogen, R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X. For example, cold, concentrated HCl and formalin are added to a stirred suspension of the steroid in chloroform, cooled to about 0 C. The mixture is then allowed to come to room temperature and stirred for several hours to afiord the corresponding 17a,20,20,21 bis(methylenedioxy) -derivative.

In a prefer-red embodiment of our invention, the 20,20,21-bis(methylenedioxy)-4-pregnene 3,11 dione compound which has the following formula:

wherein R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X, is prepared by oxidastructure O H2 I wherein R is B-halogen, ,B-hydroxy and/ or ,B-formyloxy, or keto-, but fl-halogen is present at R only when X is halogen, and R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X. In a preferred embodiment of our invention, the steroid is dissolved in a solvent such as benzene and the resulting solution is cooled to room temperature and treated with ethyl formate. The air in the system is replaced with nitrogen, sodium hydride is added and the mixture is stirred at room temperature for several hours,

The l7a,20,20,2l-bis(rnethylenedioxy) 2 hydroxytmethylene-4-pregnene-3-one compound reacts with hydrazine in an inert atmosphere to form the corresponding 17a,20,20,21-bis(methylenedioxy) 4 pregneno-[3,2-c] pyrazole.

Upon treatment of a 17a,20,20,2l--bis(methylenedioxy)- 2-hydroxymethylene-4-pregnene-3-one compound with a lower alkanol in the presence of an acidic reagent such as a p-toluenesulfonic acid the corresponding 17a,2(),20,2l bis-(methylenedioxy)-2-alkoxymethylene 4 pregnene- 3-one is formed. When the latter compound is reacted with a monosubstituted hydrazine, the corresponding N- substituted 4 pregneno-[3,2-c]pyrazole compounds are formed. The N-substituted-4-pregneno-[3,2-c1pyrazoles having structure A are designated as the 1-substituted- 4-pregneno-l3,2-c]pyrazoles, and the N-su'bstitu-tedpyrazole compounds having structure B are designated as the 2-substituted-4-pregneno-[3,2-c]-pyrazoles.

pr y I Cll2 wherein R R R and X have the significance above defined, but hydrogen is present at not more than three of the four positions R R R and X, and wherein R is an alkyl, cycloalkyl, aralkyl or an aryl group. The products formed may be separated by chromatography.

Upon treatment of a l7a,20,20,21-bis(methylenedioxy)- 2-hydroxymethylene-4-pregnene-3-one compound directly with a monosubstituted arylhydrazine, without the intermediate formation of the Z-alkoxymethylene-derivative, one isomer is generally formed in preponderant amounts, whereas when reacting the l7a,20,20,2l-bis(methylenedioxy)-2-alkoxymethylene-4-pregnene-3 one compound with a monosubstituted arylhydrazine, significant amounts of both isomers are obtained. When these reactions take place with monosubstituted alkylhydrazines, mixtures may be obtained when starting with the Z-hydroxymethylenesteroid as well as with the 2-alkoxymethylene-steroid. A mixture of isomers may also result from the reaction of a monosubstituted hydrazine with a Z-hydroxymethylenecompound which possibly contains variable amounts of the 2-alkoxymethylene-derivative due to the operating procedures employed, for example, due to recrystallization in the presence of a trace of alcohol a solution of the 2- hydroxymethylene-compound from which acid has not been completely removed.

Among the monosubstituted hydrazines which may be used for the process of our invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazine, butylhydrazines, B-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as o-, m-, and p-halophenylhydrazines, 0-, m-, and p-tolylhydrazines, 0-, m-, and p-alkoxyphenylhydrazines, 0-, m-, and p-nitrophenylhydrazines, l-hydrazinonaphthalene, Z-hydrazinopyridine, 3-hydrazinopyridine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and 2-hydrazinopyrirnidine; aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

There are thus produced the corresponding N-substituted-4-pregneno-[3,2-c]pyrazo-les including: N-alkyl such as N-methyl-, N-ethy1-, N-butyl-, N-propyl-, N-(B- hydroxyethyl)-; N-cycloalkyl-; N-arylwhich may be derived from any aromatic nucleus, including N-phenyland the N-substituted-phenyl derivatives such as o-, m-, and p-halophenyl; o-, m-, and p-tolyl-; o-, m-, and p-alkoxyphenyl-, o-, m-, and p-nitrophenyl-; N-(l"-naphthyl)-, N-(2"-pyridyl)- N-(3-pyridyl)-, N-(4pyridyl)-, N- (4-pyridyloxide)-, N-(2"-pyrimidyl)-; N-aralkyl-, such as N-benzyland N-phenylethenyl-4-pregneno-[3,2-c] pyrazoles.

The N-alkyl-4-pregneno-[3,2-c]pyrazoles may also be prepared by direct alkylation of the N-unsubstituted-4- pregneno-[3,2-c]pyrazoles.

A 17oc,20,20,21 bis(methylenedioxy)-l lfl-hydroxy-4- pregneno-[3,2-c]pyrazole which has a 9a-halo-substituent is preferably prepared by the following alternate route. Using the procedures described above, the 9a-halo-11/3,- 17a,2l-trihydroxyt-pregnene 3,20-dione is converted into the corresponding l7a,20,20,2l-bis(methylenedioxy)-9ahalo-11B-hydroxy-4-pregnene-3-one. The latter compound is then oxidized to the l7a,20,20,21-bis(methylene- 7 dioxy)-9o4-halo-4-pregnene-3,1l-dione, which is reacted with ethyl formate and sodium-hydride to form the 2- hydroxymethylene-derivative. The latter compound is reacted with hydrazine, or a monosubstitutcd hydrazine, to give the corresponding l7o4,20,20,21-bis(methylenedioxy)- 9o4-halo-ll-oxo-4-pregneno-[3,2-c1pyrazole compound, or the N-substituted derivative thereof. The latter compound is then reduced to the corresponding l7o4,2O,20,21-bis- (methylenedioxy)-94 4-halo-ll5 hydroxy 4 pregneno- [3,2-e]pyrazole compound, for example, by adding a saturated solution of sodium borohydride to a solution of the steroid in a mixture of triethylamine and isopropyl alcohol to which we prefer to add a little water, and allowing the mixture to stand overnight.

The N-unsubstituted-1704,20,2O,2l-bis(methylenedioxy)- 4-pregneno-[3,2-c]pyrazole compounds are converted into N-acyl-derivatives having the following structures:

wherein R is B-halogen, fi-hydroxy or keto, but j3-halogen is present at R only when X is halogen; R R and X have the meaning described above, but hydrogen is present at not more than three of the four positions R R R and X; and wherein R is an acyl group, by treating with an acylating agent, e.g., a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride or tertiary butyl acetyl chloride; a lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or :acetyl chloride; or a polybasic anhydride such as fifi-dimethylglutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

Upon treatment of any of the above described 1704,20, 20,21-bis(methylenedioxy)-4-pregneno [3,2-c]pyrazole compounds with a dilute organic acid, for example, a 60% aqueous solution of formic acid, the l7o4,20,20,2l-bis (methylenedioxy)-protecting group is removed and there is obtained the corresponding 17o4,2l-dihydroxy-20-oxo-4- 8 pregneno-[3,2-c1pyrazoles which are represented by structures A and B:

OIIzOR:

CHzOR wherein R is fi-halogen, B-hydroxy or keto, but fi-halogen is present at R only when X is halogen; R R and X have the meaning described above; but hydrogen is present at not more than two of the three positions R R and X, and wherein R is acyl, alkyl, cycloalkyl, aryl or aralkyl and R is hydrogen, an acyl group corresponding to the organic acid used in this reaction, or a mixture of the two.

Any acyl groups present at R; and/or at R may be removed by treating the steroid with sodium methoxide in methanol at room temperature to form the corresponding l704,21-dihydroxy-2O-oxo-4-pregneno-[3,2-c]pyrazole. Acyl groups present at the R position may be selectively removed by treatment with aqueous acetic acid.

The compounds of our invention include, among others, the following:

9 900-fiur-o-1113,1700,21-trihydr0xy-16-Inethylene-20-oxo-4- pregneno-[3 ,2-c] pyrazole, 900-chloro-11/3,1700,21-trihydroxy-2O-oxo-4-pregneno- [3,2-c]pyrazole, 900-chloro-l15,1700,21-trihydroxy-1600-1nethy1-20-oxo-4- [3,2-c]pyrazole, 900-chloro-115,1700,21-trihydroXy-l6/3-methyl-20-oxo-4 pregneno-[3 ,2-c] yrazole, 900-chloro-11B,1700,2l-trihydroxy-l6-methylene-2O-oXo-4- pregneno- [3,2-c] pyrazole, 900-fluoro-1113,1700,21-trihydroxy-60t-methyl-20-oxo-4- pregneno- [3 ,2c] pyrazole, 900-fluoro-11B,1700,21-trihydroxy-600,1600-dimethy1-20-oX0- 4-pregneno-[3,2-c]pyrazole, 900-fluoro-11B,1700,21-trihydnoxy-600,163-dimethyl-2O-oxo- 4-pregneno-[3 ,2-c] pyrazole, 90x-fluor0-1lfi,l700,2l-trihydroxy-600-rnethyl-16-tnethylene- -oXo-4-pregneno- [3,2-c1pyrazole, 900-chloro-11/3,1700,21-trihydroxy-600-methyl-20-oxo-4- pregneno- [3 ,2-c] pyraz'ole, 900-chloro-11,8,1700,21-trihydroxy-600,1600-dimethyl-20-oXo- 4-pregneno- [3 ,2-c]pyrazole, 900-chloro-11,8,1700,21-trihydroxy-600,165-diinethyl-20-oxo 4-pregneno- [3 ,2-c] pyrazole, 900-chloro-1113,17a,21-trihydroXy-600-methyl-16-methylene-20oxo-4-pregneno- [3 ,2-c] pyrazole, 900-chloro-600-fluor-o-11B,1700,21-trihydroxy-20-oxo-4- pregneno- [3 ,2-c pyrazole, 900-chloro-600-fluoro-11,8,1700,21-trihydroxy-16o0-rnethyl- 20-oxo-4pregneno- [3 ,2-c] pyrazole, 900-chloro-600-fluoro-1 1,6,1700,21-trihydroxy- 1 6,8-n1ethyl- 20-oxo-4-pregneno- [3 ,2-c pyrazole, 900-chloro-600-fluoro-1 lfi1700,21-trihydroxy-16-1nethylene- 20-oxo-4-pregneno-[3,2-clpyrazole, 600,900-difiuoro-11fl,1700,21-trihydroxy-20-oxo-4-pregneno- [3 ,2-c] pyrazole, 600,900-difluoro-115,1700,2l-trihydroxy-l600-n1ethyl-2O-oXo- 4-pregneno- [3 ,2-c] pyrazole, 600,900-difiuoro-11B,1700,21-trihydroXy-l6,8-methyl-20- oXo-4-pregneno-[3,Z-clpyrazole, 600,900-difiuoro-115,17u2l-trihydroxy-l6-rnethylene-2O- oxo-4-pregneno-[3,2-c]pyrazole,

and the ll-oxo-analogues of all of the above compounds, the

900,11B-dichloro-1700,21-dihydroxy-20-oxo-4-pregneno- [3 ,2-c] pyrazole,

900,1 lli-dichloro-l700,21-dihydroxy-1600-methyl-20-oxo-4- pregneno- [3 ,2-c] pyrazole,

900,1 lfi-dichloro-1700,21-dihydroxy-16B-rnethyl-2O-Oxo- 4-pregneno- 3 ,2-c1pyrazole,

900,1 1B-dichl oro-1700,21-dihyd'roxy-16-methylene-20-oxo- 4-pregneno- [3 ,Z-c] pyrazole,

900,11fi-dichloro-600-fluor0-1700,21-dihydroxy-20-oXo-4- pregneno- [3 ,2-c] pyrazole,

900,11/3-dichloro-600-fluoro-1700,2l-clihydroxy-l600-1nethy1- 20-oxo-4-pregneno- [3 ,2 c] pyrazole,

900,11/3-dichloro-600-fluoro-1700,21-dihydroxy-16fi-methyl- 20-oXo-4-pregneno [3 ,2-c] pyrazole,

900,11fl-dichloro-600-fluoro-1700,21-dihydroxy-16-methylene-20-oxo-4-pregneno- [3 2:2] pyrazole,

900,1I/E-dichloro-1700,21-dihydroxy-600-methyl-20'oxo-4- pregneno- 3 ,2-c] pyrazole,

900,11,8-dichloro-1700,21-dihydroXy-600,1600-dinicthyl-2O- oxo-4-pregneno- [3 ,2-c] pyrazole,

900,1lfl-dichloro-1700,21-dihydroxy*60t,16fl-dirnethyl-20- oxo-4-pregneno- [3 ,2-c] pyrazole,

900,115-dichloro-1700,21-dihydroXy-600-methyl-16methylene-20-oXo-4-pregneno- [3 ,2-c] pyrazole,

900-bromo-1 1/3-chloro-l700,21-dihydroxy-2O-oxo-4-pregneno- [3 ,Z-c] pyrazole,

900-brorno-11 3-chloro-1700,Zl-dihydroxy-1600-methyl-2O- oxo-4-pregneno- [3 ,2-c] pyrazole,

900-bromo-1IB-chloro-1700,21-dihydroxy-16,8-methyl-2O- oxo-4-pregnen o- [3 ,2-c] pyrazole,

ll il 900-bromo-11/3-chloro-1700,21-dihydroxy-16-methylene- 20-oXo-4-pregneno-[3 ,2-c]pyrazole, 900-bromo-l1fl-chloro-600-fiuoro-1700,21-clihydroXy-20-oxo- 4-pregneno- [3 ,2-c] pyrazole, 900-bro1no-1 1fl-chloro-600-fluoro-170x,21-dihydroxy-l 6o0- methyl-20-oxoA-pregneno-[3,2-c1pyrazole, 900-bromo-1 1fl-chloro-600-fluoro-1700,2l-dihydroxy-16,8-

methyl-20-oXo-4-pregneno-[3,2-c1pyrazole, 900-bromo-11/3-chloro-600-fluoro-1700,21-dihydroxy-16- methylene-20-oxo-4-pregneno- 3 ,2-c] pyrazole, 900-bromo-l lfi-chloro-:0,21-dihydroxy-6o0-methyl-20- oxo-4-pregneno-[3,2-c]pyrazole, 900-bromo-11fl-chloro-1700,21-dihydroxy-600,1600-dimethyl- 20-oXo-4-pregneno- 3 ,2-c] pyrazole, 900-brom o-11/3-chloro-1700,2l-dihydroxy-600, 16fi-dimethyl- 20-oXo-4-pregneno-[3,2-c]pyrazole, and 900bromo-l1,8-chloro-1700,21-dihydroXy-600-methyl-l6- methylene-ZO-oxo-4-pregneno-[3 ,2c] pyrazole as well as the 1'- and 2-alkyl-, the 1'- and 2-cycloalky1-, the 1'- and 2'-aryl-, and the 1'- and 2'-aralkyl derivatives of all of the above named compounds.

The N-acyl-derivatives of the above described 1700,21- dihydroxy 20 oxo 4 pregneno [3,2 c]pyrazoles are preferably obtained by treating the corresponding N acyl 1700,20,20,2l bis(methylenedioxy) 4 pregneno [3,2 clpyrazole compound with a diluteorganic acid to remove the 1700,20,20,21 bis(methylenedioxy)- protecting group.

The 21 acyl derivatives of the above described 1700,21- dihydroxy 20 oxo 4 pregneno [3,2 c]pyrazoles in which R is H may be prepared by heating an N acyl- 1700,21 dihydroxy 20 oxo 4 pregneno [3,2 c] pyrazole 21-acylate with aqueous acetic acid, whereupon the N-acyl group is selectively removed.

The N -acyl 21 acylate derivatives of the above described 1700,21 dihydroxy 20 oxo 4 pregneno- [3,2 c] pyrazoles in which both acyl groups are the same may be prepared 1) by reacting a 1700,21 dihydroxy- 20 oxo 4 pregneno [3,2 clpyrazole with two equivalents of an acylating agent or (2) by reaction of an N-acyl- 1700,21 hydroxy 20 oxo 4 pregneno [3,2 cJpyrazole with one equivalent of an acylating agent in which the acyl group of the acylating agent is the same as the acyl group already present at the N-position of the pyrazole.

The N-acyl-21-acylate derivatives of the above described 1700,21 dihydroxy 20 oxo 4 pregneno [3,2 c]pyrazoles in which the acyl groups are different are prepared by reaction of an N acyl 1700,21 dihydroxy 20- oxo 4 pregneno [3,2 cjlpyrazole with an acylating agent in which the acyl group of the acylating agent is ditferent from the acyl group already present at the N-position of the pyrazole.

Acylating agents which can be used for this purpose include a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride, tertiary butyl acetyl chloride; 21 lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or acetyl chloride; or a polybasic anhydride such as 3,5- dimethyl-glutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

The 1700,21 dihydroxy 20 oxo 4 pregneno- [3,2-c]-pyrazole is reacted with methanesulfonyl chloride in a non-aqueous base to form the 21-mesylate. A steroid in which R is hydrogen is preferably converted to the N-acyl derivative before undergoing this reaction.

The 1700,21 dihydroxy 20 oxo 4 pregneno- [3,2-c]-pyrazole 21-rnesylate is heated with an alkali iodide to form the 2l-iodo-compound. In a preferred method for carrying out this reaction, sodium iodide is added to the steroid dissolved in acetone and the resulting mixture is heated at a reflux temperature for approximately one hour.

The 1700 hydroxy 21 iodo 20 oxo 4 pregneno- [3,2-c]-pyrazole is heated with an alkali bisulfite in a '13 9a-bromo-1lp-chloro-l7a-hydroxy-6a-methyl-16- methylene-ZO-oxo-4-pregneno- 3,2-c1pyrazole, as well as the 1- and 2'-alkyl-, and the 1'- and 2-cyc1oalkyl-, the 1- and 2'-aryl-, the 1- and 2'-aralkyland the N-acylderivatives of all of the above named compounds.

The ZI-dihydrogen phosphate esters are prepared by the reaction of the corresponding 21-iodo compound with a mixture of silver phosphate and phosphoric acid. Both the moneand dialkali metal salts may be obtained by neutralization of the dihydrogen phosphate ester with an alkali me'thoxide. Treatment with additional amounts of alkali methoxide will convert an N-acyl-steroid into the free amine (R :H) dialkali .metal salt from which the dihydrogen phosphate can be obtained by contacting with an ion exchange resin.

The A, B, C and pyrazole rings are not shown in the above equation, as the substituent groups on these rings do not affect the course of reaction and in general are unchanged during reaction. R has the meaning above defined and X is halogen.

The 21-fluoro-17a-hydroxy-20-oxo-4-pregneno-[3,2-c]- pyrazoles are prepared from the corresponding 17oc,2ldihydroxy-20-oxo-4-pregneno-[3,2-c] pyrazole 21-mesylate by heating with an alkali fluoride in a solvent to form. a mixture of a l7u,2l-epoxy-compound and the corresponding 21-fiuoro compound. These compounds are separated by partition chromatography, or by chromatography on a weak adsorbent such as silica gel. There is thus obtained the 21-flu0ro-derivatives of all of the compounds named in columns 2, 3, and 4.

The 21-fiuoro-derivatives are represented by structures A and B:

' acetate.

wherein R R R R and X have the significance above described. All of the 4-pregneno-[3,2-c1pyrazoles described in the foregoing structures form salts such as the hydrochloride, sulfate, chlorate, perchlorate, picrate and trichloroacetate, on treatment with the corresponding acid. Formation of crystalline salts, especially the hydrochloride salts, provides a means of isolating the 4-pregneno-[3,2-c]- pyrazoles.

A further embodiment of our invention comprises novel pharmaceutical compositions containing the novel 4-pre-gneno-[3,2-c]pyrazoles exemplified in the foregoing structures.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation. Details of the above described reactions are to be found in the examples.

Example 1 To a suspension of 25.0 g. of 11fl,17a,21-trihydroxy- 16a-methyl-4-pregnene-3,2(l-dione in 1.5 1. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzene-n-hexane 111). A 2.425 g. aliquot'is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,-20,21-bis(methylenedioxy)-11B- hydroxy-l6a-methyl-4-pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

A'solution of 400 mg. of 17a,20,20,21-bis(methylenedioxy -1 1,8-hydroxy-16a-methyl-4-pregnene-3-one in 4- ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17a,20,20,21-bis(methylene)-l6a-methyl-4-pregnene-3,11-dione.

The 17a,20,20,21 bis(met.hylenedioxy)-16a-methyl-4- pregnene-3,11-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again aciditied with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21 bis(methylenedioxy) -2-hydroxyrnethylene- 16a-methyl-4-pregnene-3,1 l-dione.

The 17a,20,20,21 bis (methylenedioxy) 2 hydroxymethylene 16cc methyl 4 pregnene 3,11 dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a-20,20,21-bis(methylenedioxy)- 16u-methyl-l 1-ox0-4-pregneno- 3,2-c] pyrazole.

To a solution of 100 mg. of 17a-20,20,21-bis(methylenedioxy) 16oz methyl 11 oxo 4 pregneno- [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (un til the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate, The solvent is then distilled at about 40 C. in vacuo to afford the N- acetyl 17a,20,20,2l bis(methylenedioxy) 16a methyl-l1-oxo-4-pregneno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acyl-derivative.

The N acetyl 17a,20,20,21 bis(methylenedioxy)- 16oz methyl 11 oxo 4 pregneno [3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl-17a-21-dihydroxy-l6ot-methyl-l1,20- dioxo 4 pregneno [3,2-c]pyrazole and N acetyl- 21 formyloxy 17a hydroxy 16a methyl 11,20 dioxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17u,21-dihydroxy 16a methyl 11,20 dioxo 4 pregneno- [3,2-c]pyrazole.

To a solution of 100 mg. of N-acetyl-17a-21-dihydroxy- 16a methyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate, The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13),

saturated aqueous sodium bicarbonate (until the :pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17ot,21-di- The alkoxide is neutralized with hydroxy 16a methyl 11,20 dioxo 4 pregneno- [3,2-c]pyrazole 2l-acetate which is isolated by the addi tion of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl 17a-2l dihydlroxy 16a methyl 11,20 dioxo-4-pregneno-[3,2-c]pyrazole 2l-acylate.

In accordance with the above procedure, but starting with the 1704,21 dihydroxy 16m methyl 11,20 dioxo-4-pregneno-[3,2-c]pyrazole, and using two milliequivalents of another acylating agent there is obtained the corresponding N-acyl-2lacylate thereof.

A solution of 5.73 g. of N-acetyl-l7a,21-dihydroxy- 16a methyl 11,20 dioxo 4 pregneno [3,2-c'jpyrazole 2l-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extracts are washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 17a,2l-dihydroxy-l6a-methyl- 11,20-dioxo-4-pregneno-[3,2-c]1pyrazole 21-acetate.

To a solution of mg. of N-acetyl-l7a-21,-dihydroxy- 16a methyl 11,20 dioxo 4 pregneno [3,2-c1pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-aeetyl-l7a,2l-dihydroxy-la-methyl- 11,20-dioxo-4-pregneno-[3,2-c1pyrazole 2 l-mesylate.

To a 180 mg. of N-acetyl-17a,2l-dihydroxy-l6a-methyl 11,20 dioxo 4 pregneno [3,2-clpyrazole 21- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted wit-h water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-17a-hydroxy-21-iodo-16a-methyl-l1,20- dioxo-4-pregneno-[3,2-c]pyrazole.

The N-acetyl-l7a-hydroxy-2l-iodo-l6a-methyl-11, 20- dioxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l7a-hydroxy-16umethyl-11,20-dioxo-4-pregneno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17a-hydroxy-16a-methyl- 11,20-dioxo-4-pregneno- 3,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-17a,21-dihydroxy- 16a-methyl-11,20-dioxo- 4- pregneno [3,2-c1pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17a,21-epoxy- 16u-methyl-11,20-dioxo-4-pregneno [3,2-c]pyrazole and N-acetyl-Zl-fluoro-17a-hydroxy-16u-methyl 11,20-dioxo- 4-pregneno-[3,2-clpyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg, aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 21-fiuoro-17ot-hydroxy- 16a-methyl-1 1,20-dioxo-4-pregneno-[3,2-c] pyrazole.

In accordance with the above procedures, but starting with the 11/3,l7a,2l-trihydroxy-16fl-methyl-4-pregnene- 3,20-dione in place of the 11B,17tx,21-trihydroxy-16amethylene-4-pregnene-3,20-dione, there are obtained as products the corresponding 17a,21-dihydroxy-165-methyl- 11,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acylthe 2l-acylate, and the N-acyl-21-acylate derivatives thereof; 17u-hydroxy-16fl-methyl-11,20 dioxo 4 pregneno- [3,2-c] pyrazole and the N-acyl-derivatives thereof; and the 21-fluoro-17a-hydroxy 16/3 methyl 11,20 dioxo-4- pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting with the 11,8,17a,2l-trihydroxy-16-methylene-4-pregnene- 3,20-dione in place of the 11,8,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dione, there are obtained as products the corresponding 17tx,2l-dihydroxy-16-methylene- 11,20-dioxo-4-pregneno-[3,2 c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-21-acylate derivatives thereof; the 17a-hydroxy-16-methylene 11,20 diox-o-4-pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 21-fiuoro-17a-hydroxy-16-methylene-11,20-dioxo- 4-pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

Example 2 To a suspension of 25.0 g. of 6a-fiuoro-11fi,17a-21-trihydroxy-4-pregnene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of Formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give Ga-fluoro-17a,20,20,21-bis(methylenedioxy) l1 fl-hydroxy-4-pregnene-3-one, which is used in the subsequent step of the synthesis Without further purification.

The 17ot,20,20,21bis(methylenedioxy) -6a-fluoro-1 1,8- hydroxy-4-pregnene-3-one (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate.

The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 170;,20, 20,21-bis(methylenedioxy)-6a-fluoro 11B hydroxy 2- hydroxymethylene-4-pregnene-3-one.

The 17a,20*,20,21bi$ (methylenedioxy) -6a-fluoro-1 118- hydroxy-2-hydroxymethylene-4-pregnene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17ot,20,20,21-bis(methylenedioxy)-6ufluoro 11B hydroxy 4 pregneno [3,2-c]pyrazole.

To a solution of mg. .of 17a,20*,20,21-bis(methylenedioxy) 60c fluoro 11B hydroxy 4 pregneno- .[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afiord the N-acetyl- :,2O,20,21 bis(methylenedioxy) 6a fluoro 11B- hydroxy-4-pregneno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N racetyl 17a,20,20,21 bis(methylenedioxy)- 6u fluoro 11,8 hydroxy 4 pregneno [3,2-c1pyrazole (72 0 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of N- acetyl 60 fluoro 11,8,17oc,21 trihydroxy 20 oxo- 4-pregneno-[3,2-c1pyrazole and N-acetyl-6u-fluoro-21- formyloxy 11fl,17u dihydroxy 20 oxo 4 pregneno- [3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6oc-fi1l0IO-11B,17oc,21-tli hydroxy-ZO-oxo-4-pregneno- 3 ,2-c] pyrazole.

To a solution of 1-00 mg. of N-acetyl-6a-fluoro-1113,17, 21-trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-6a-fiuoro-l1B,17x,21-trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole 21 acetate which is isolated by addition of water and filtration.

In accordance with the above procedures, but using the equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N acetyl 6a fluoro 11,3,17a,21 trihydroxy 20- oxo-4-pregneno- 3,2-c] pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 6a-fluoro-1113,17ot,21-trihydroxy-20-oxo-4-pregneno[3,2-c]pyrazole, and using two equivalents of another acylating agent there is obtained the corresponding N- acyl-21-acylate thereof.

A solution of 5.73 g. of N-acetyl-6a-fluoro-11p,17-u,21- trihydroxy-20-oxo-4-pregneno- 3,2-c] pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 60: fluoro 11,3,17a,2l trihydroxy 20 oxo 4- pregneno-[3,2-c]pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-6ot-fluoro-llfl,17a, 21 trihydroxy 20 oxo 4 pregneno [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-6ot-fluoro-11p,17a,21-trihydr0xy-20- oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate.

To 180 mg. of N-acetyl-6ot-fluoro-11fi,17u,21-trihydroxy-20-oxo-4-pregneno-[3,2-c] pyrazole 2l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl- 60c fluoro 11,8,17u dihydroxy 21 iodo 20 oxo- 4-pregneno-[3,2-c1pyrazole.

The N-acetyl-6a-fluoro-11 8,17u-dihydroxy-21-iodo-20 oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture isheated under reflux for a period of about one hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-6a-fluoro-11/3, 17a-dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium 'methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6ot-fluoro-11B,17adihydroxy-20oxo-4-pregneno- [3 ,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-6ot-fluoro-l15,17a, 21 t-rihydroxy 20 oxo-4-pregneno-[3,2-c]pyrazol-e 2lrnesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17a,21-epoxy- Got-flUOI'O-l 1B=hydroxy-20-oxo-4-pre-gneno-[3,2-c1pyrazole and N-acetyl-6a,2l-difluoro-l113,17ot-dihydroxy-20-oxo-4- pregneno[3,2-c]pyrazole which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the corresponding N-acyl derivatives, there are obtained as products the N-acyl-6u-fiuoro-11B,17ot-di-hydroxy-20-oxo-4-pregneno-[3, 2-c]pyrazole and the N-acyl- 6a,21-difluoro-11fl,l7u-dihydroxy-20-oxo 4 pregneno- [3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with nhexane. The residue is washed with water, filtered and dried to constant weight to give the 60,2l-CliflLlOIO-llfl, 17w dihydroxy-20-oxo-4-pregneno- 3,2-c] pyrazole.

In accordance with the above procedures, but starting with the 111,6,17a,2l-trihydroxy-da,16a-dimethyl-4-pregnone-3,20-dione in place of the 6a-fluoro-1lB,17u,21-trihydroxy-4-pregnene-3,ZO-dione there are obtained as products the corresponding 11,8,l7ot,21-trihydroxy-6a,16ot-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole and the N- acyl, the 21-acylate, and the N-a-cyl-21-acylate derivatives thereof; the 11B,17o-dihydroxy 1 6a 'dimethyl-20-oxo-4- pregneno-[3,2-c]pyrazole and the N-acyl derivative thereof; and the 21-fluoro-11fl,l7ot-dihydroxy-6a,l6a-dimethyl- 20-oxo-4-pregneno-[3,2-c]pyrazole, and the N-acyl derivative thereof.

Example 3 To a suspension of 25.0 g. of 1 1B,17a,21-trihydroxy- 6a-methyl-4-pregnene-3,20-dione in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperst-rip chromatography but shows two U.V. absorbing spots near the solvent from (methanol-formamide 2:1 vs. benzenen-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,21 bis(methylenedioxy) 11/3 hydroxy-6amethyl-4-pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,20,21-bis(methylenedioxy)-11e-hydroxy-6amethyl-4-pregneno-3-o11e in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice With ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17a,20,20,21-bis (methylenedioxy)-6a-methyl-4-pregnene-3,1 l-dione.

The 17a,20,20,21 bis(methylenedioxy) 60c methyl- 4-pregnene-3,11-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 1700,20,20,21 bis(methylenedioxy) 2 hydroxymethylene 600 methyl 4 pregnene 3,11 dione.

The 1700,20,20,21 bis(methylenedioxy) 2 hydroxymethylene 600 methyl 4 pregnene 3,11 dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a,20,20,21 bis(methylenedioxy) 600 methyl 11 oxo 4 pregneno [3,2-c1pyrazole.

To a solution of 100 mg. of 1700,20,20,21 bis(methylenedioxy) 600 methyl 11 x0 4 pregneno [3,2- c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (un til the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo to afford the N- acetyl 1700,20,20,21 bis (methylenedioxy) 600 methyl- 1l oxo 4 pregneno [3,2-c1pyrazole, which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl l70t,20,20,21 bis(methylenedioxy) 60 methyl 11 oxo 4 pregnene [3,2-c]pyrazole (720 mg.) is heated on a steam bath with 24 ml. of a 60% solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N acetyl 1700,21 dihydroxy 60 methyl- 11,20 dioxo 4 pregneno [3,2-c1pyrazole and N- acetyl 21 f-ormyloxy 1700 hydroxy 600 methyl- 11,20 dioxo 4 pregneno [3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 1700,21- dihydroxy 60 methyl 11,20 dioxo 4 pregneno- [3,2-c1pyrazole.

To a solution of 100 mg. of N acetyl 1700,21 dihydroxy 600 methyl 11,20 dioxo 4 pregneno [3,2-

c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is l-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N- acetyl 1700,21 dihydroxy 600 methyl 11,2 0 dioxo- 4 pregneno [3,2-c]pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl 1700,21 dihydroxy 600 methyl 11,20- dioxo 4 pre-gneno [3,2-c1pyrazole 21-acylate.

In accordance with the above procedures, but starting with the 1700,21 dihydroxy 600 methyl 11,20 dioxo- 4 pregneno [3,2-c]pyrazole, and using two milliequivalents of another acylating agent, there is obtained the corresponding N acyl 17OL,21 dihydroxy 600 methyl- 11,20-dioxo-4-pregneno- [3,2-c1pyrazole 21-acylate.

A solution of 5.73 g. of the N acetyl 1700,21 dihydroxy 60 methyl 11,20 dioxy 4 pregneno [3,2- c]pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 m1. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 1700,21 dihydroxy 60 methyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole 21- acetate.

To a solution of mg. of N-acetyl-17a,21-dihydroxy- 600-methyl-11,20-dioxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-l7fl,21-dihydroxy-600-methy1-11,20- diox-o-4-pregneno- [3,2'c] pyrazole 21-mesylate.

To mg. of N-acetyl-1700,21-dihydroxy-600-methyl- 11,20-dioxo-4-pregneno-[3,2-c]pyrazo1e 21-mesylate dissolved in 10 m1. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N- acetyl 1700 hydroxy 21 iodo 600 methyl 11,20- dioxo-4-pregneno- 3 ,2-c] -pyrazole.

The N-acetyl-17 0t-hydroxy-21-iod-o-6a-methyl-1 1,20-dioxo-4-pregneno-[3,2-c1py-razole is dissolved in a mixture of 5 ml. of water and 5 m1. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l70- hydroxy 600 methyl 11,20 dioxo 4 pregnene-[3, 2-c1pyraz-ole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and all-owed to react with 0.9 ml. of 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17ot-hydroxy-6a-met'hyl- 11,20-dioxo-4-pregneno-[3,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-Null-dihydroxy- 6oz methyl 11,20 dioxo 4 pregneno [3,2 c]pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the pro-duct is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-l7a, 21 epoxy 60c methyl 11,20 dioxo 4 pregneno- [3,2-c]pyrazole and N-acetyl-Z1-fiuoro-17a-hydroxy-6amethyl-11,20-dioxo-4-pregneno [3,2 c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the 9ot-fluoro-1 1,6,17o,21-trihydroxy-4-pregnene-3,20- dione in place of the 11B,17a,21-trihydroxy-4-pregnene-3, 20-dione there are obtained as products the corresponding 90: fiuoro-17a,21-dihydroxy-1l,20-dioxo-4-pregneno- [3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 90t-flllOI'O- 17a-hydroxy-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 9a,21-di1luoro- 17 a hydroxy 11,20 dioxo 4 pregneno [3,2 c] pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting With the 9u-fiuoro 60c methyl-1lB,l7a,21trihydroxy-4- pregnene-3,20-dione in place of the 11B,17a,21-trihydroxy-6a-methy1-4-pregnene-3,20-dione, there are obtained as products the corresponding 9a-fiuoro-17a,21-dihydroxy- 60 methyl-11,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-fluoro-17a-hydroxy-6a-methyl-l1,20-dioxo-4-pregneno-[3,2-c1pyrazole and the N-acyl derivatives thereof; and the 9a,2l-difiuoro-Hot-hydroxy- 60c methyl 11,20 dioxo 4 pregneno [3,2 c]pyrazole and the N-acyl derivatives thereof.

Example 4 To a suspension of 25.0 g. of 1l5,17a,21-trihydroxy 16a-methyl-4-pregnene-3,20-dione in 1.5 liters of alcoholfree chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography. A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,2l-bis(methylenedioxy)-llp-hydroxy-16w rnethyl-4-pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

The 17a,20,20,21 bis(methylenedioxy)-1lfi-hydroxy- 16a-methyl-4-pregnene-3-one (1.350 g.) is dissolved in 25 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17u,20,20,21 bis (methylenedioxy) 115 hydroxy 2 hydroxymethylene-l6ot-methyl-4-pregnene-3-one.

The 17a,20,20,21 bis(rnethylenedioxy)-11B-hydroxy- 2-hydroxymethylene-16a-methyl-4-pregnene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17a,20,20,21-bis(methylenedioxy) 11,8 hydroxy 160a methyl 4 pregneno-[3,2-c1pyrazole.

To a solution of mg. of 17u,20,20,21-bis(methylenedioxy) hydroxy 16a methyl 4 pregneno- [3,2-c]-pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N acetyl 17o,20,20,21 bis(methylenedioxy) 11,6- hydroxy-16a-methyl-4-pregneno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride there is obtained the corresponding N-acyl-steroid.

The N acetyl 17a,20,20,21 bis(methylenedioxy)- 11;? hydroxy 16oz methyl 4 pregneno [3,2-c] pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl-11 5,1701,- 21-trihydroxy 16cc methyl 20 oxo 4 pregneno- [3,2 c]pyrazole and N acetyl 21 formyloxy- 1113,17a dihydroxy 16a methyl 20 oxo 4 pregneno-[3,2-c1pyrazole which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 m1. of cure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 11,8,17a,21 trihydroxy 16a methyl 20 0x0 4- pregneno-[3,2-c]pyrazole.

To a solution of 100 mg. of N-acetyl-11fl,17 x,21- trihydroxy 16a methyl 20 oxo 4 pregneno- [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand over-night at room temperature. A mixture of ice and water is then added. After standing for about evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17u,20,20,21-bis(methylenedioxy)-9a,1lfl-dichloro 4 pregneno-[3,2-c1pyrazole.

To a solution of 100 mg. of 17u,20,20,21-bis(methylenedioxy)-9a,1la dichloro 4 pregneno [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of propionic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aquelayer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-propionyl 17cc,20,20,21 bis(methylenedioxy) 9a,11B-dichloro-4-pregneno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of propionic anhydride, there is obtained the corresponding N-acyl-derivative.

The N-propionyl 17 oz,20,20,21 bis(methylenedioxy) 9a,115-dichloro-4-pregneno-[3,2-c]pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-propionyl-9a,115-dichloro 17a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c] pyrazole and N-propionyl-9a,11,Bdichloro- 21-formyloxy 170a hydroxy-20oxo-4-pregneno-[3,2-c] pyrazole, which compounds are separated by chromato graphy.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 90:, 11,8-dichloro 170:,21 dihydroxy 20 oxo-4-pregneno- [3,2-c] pyrazole.

To a solution of 100 mg. of N-propionyl-9ot,1l5-dichloro-17a,21-dihydroxy 2O oxo 4-pregneno-[3,2-c]- pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is l-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo. The product is then crystallized from a solvent; alternately, the product may be chromatographed on alumina to give the N-propionyl- 904,115 dichloro 17u,21-dihydroxy-20-oxo-4-pregneno- [3,2-c]pyrazole 21-acetate, which is isolated by crystallization of the appropriate eluate.

In accordance with the above procedure, but using an equivalent quantity of any other acylating agent in place of the acetic anhydride, there is obtained the corresponding N-propionyl 90,l1fi dichloro-17a,21-dihydroxy-20-oXo-4-pregneno-[3,2-c]pyrazole 2l-acylate.

In accordance with the above procedures, but starting by filtration.

28 with the 9a,11,8 dichloro 17 a,21 dihydroxy 20-oxo- 4-pregneno-[3,2-c1pyrazole and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-21-acylate thereof.

A solution of 5.73 g. of N-propionyl-9a,1lfi-dichloro- 17a,21-dihydroxy 20 oxo 4-pregneno-[3,2-c1pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting prod uct affords ,11fi-diChlOI'O :,21 dihydroxy-20-oxo- 4-pregneno-[3,2-c] pyrazole 21-acetate.

To a solution of 85 mg. of N-propionyl-9a,11B-dichloro 170:,21 dihydroxy 20 oxo-4-pregneno-[3,2-c] pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-propionyl-9a,1lB-dichloro-17a,21-dihydroxy 20 oxo 4 pregneno-[3,2-c] pyrazole 21-mesylate.

To mg. of N-propionyl-9a,11,8-dichloro-17a,21- dihydroxy 20 oxo 4 pregneno [3,2-c]pyrazole 21-mesylate dissolved .in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-propionyl-9u,11,8-dichloro-17ahydroxy-21-iodo-20-oxo-4-pregneno-[3,2-c1pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl-9a,11t?-dichloro l7ot-hydroxy 21 iodo-20-oxo- 4pregneno-[3,2-c1pyrazole.

The N-propionyl 9u.11fi-dichloro 17u-hydroxy-21 iodo-20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisullite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered The product is washed with water, dried and recrystallized from ethyl acetate to give N-propionyl 9vt,1 lfi-dichloro 17a-hydroxy-20-oxo-4 pregneno[3,2-c] pyrazole.

To a solution of 62 mg. of N-propionyl-9u,11/3-dichloro-17a,21dihydroxy 20-oxo-4 pregneno[3,2-c]pyrazole 21-rnesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-propionyl- 90:,1lfi-dichloro-lhJl-epoxy 20-oxo-4-pregneno-[3,2-c] pyrazole and N-propionyl-9oc,11,8-dichloro-2l-fiuoro-17ahydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9

ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N acetyl-l1p,17a,21-trihydroxy-l6tx-methyl-20-oxo- 4-pregneno-[3,2-c]pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl-l1B,17a,2l-trihydroxy-16a-methyl-20- oxo-4-pregneno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 1lfi,17u,21-trihydroxy-l6a-methyl-20-oxo-4- pregneno-[3,2-c]pyrazole and using two milliequivalents of another acylating agent there is obtained the corresponding N-acyl 11,8,17a,2l-trihydroxy-16a-methyl-20- oxo-4-pregneno- [3,2-c] pyrazole 21-acylate.

A solution of 5.73 g. of N-acetyl-l1fl,17a,21-trihydroxy 16oz methyl-20-oxo-4-pregneno-[3,2-c]pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 11f3,17ot,21 trihydroxy-16u-methyl-20-oxo-4- pregneno- [3 ,2-c] pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-llfl,17a,21-trihydroxy 16a-rnethyl-Z0-oxo-4-pregneno-[3,2-c] pyrazole in 0.5 ml. of pyridine, cooled to C., is added 0.015 ml. of methane slufonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-l1,8,17u,2l-trihydroxy-16u-methyl- 20-oxo-4-pregneno-[3,2-c] pyrazole 21-mesylate.

To 180 mg. of N-acetyl-l1B,17a,21-trihydroxy-16amethyl 20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-HCBtYl-llfi,17OL-dlhydl'OXy-2l-iOdO-16OL-1'I'1BthYl-20- oxo-4-pregneno-[3,2-c]pyrazole.

The N acetyl-ll5,17x-dihydroxy-2l-iodo-16a-methyl- 20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l 15, 17a dihydroxy 16u-methyl-20-oxo-4-pregneno-[3,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-11/i,17u,21-trihydroxy 20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17a,2l-epoxy- 116 hydroxy 160a methyl-20-oxo-4-pregneno-[3,2-c] pyrazole and N-acetyl-Zl-fiuoro-l1fi,17a-dihydroxy-16amethyl-20-oxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the N-acetyl-21-fluoro-1118,17udihydroxy 16a methyl-20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give the 2l-fluoro-11B,Wot-dihydroxy-16ot-methyl-20- oxo-4-pregneno- [3 ,2-c] pyrazole.

In accordance with the above procedures, but starting with the 115,17ot,21-trihydroxy-6a-methyl-4-pregnene 3, 20 dione in place of the 1l{3,l7a,21 dihydroxy-16amethyl-4-pregnene-3,20-dione, there are obtained as products the corresponding 11/3,17a,21-trihydroxy-6a-methyl- 20-oxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 115,17tx dihydroxy-6a-methyl-20-oxo-4-pregneno-[3, 2-c[pyrazole and the N-acyl derivatives thereof; and the 21 fluoro 115,17ot-dihydroxy-6ot-methyl-20-oxo-4-pregneno- [3,2-c]pyrazo1e and the N-acyl derivatives thereof.

Example 5 To a suspension of 10 g. of 9a,11/3-dichloro-17a,21-dihydroxy-4-pregnene-3,20-di-one in 475 ml. of alcoholfree chloroform and 300 m1. of methylene chloride, cooled to about 5 C. in an ice bath, is added with constant stirring 189 ml. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed with water, then with a 5% solution of sodium bicarbonate and again with water. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and n hexane to give 17a,20,20,21 bis (methylenedioxy)-9a,11fi-dichloro-4-pregnene-3-one.

The 17a,20,20,2l bis(methylenedioxy) 9a,11/3 dichloro-4-pregnene-3-one (500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and filled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are Washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as a sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give :,20, 20,21 bis(methylenedioxy)-9u,11fl-dichloro-2-hydroxymethylene-4-pregnene-3-one.

The 17a,20,20,21 bis(methylenedioxy) 901,115-dichloro-2-hydroxymethylene-4-pregnene-3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl-9a,ll,8- dichloro-2l-fluoro-17a-hydroxy 20-oxo-4-pregneno[3,2- c]pyrazole.

In accordance with the above procedures, but starting with the 9u-bromo-1lfi-chloro-17a,21-dihydroxy-4-pregnene-3,20-dione in place of the 9u,11fl-dichloro-17a,21- dihydroxy-4-pregnene-3,20-dione there are obtained as products the corresponding 90t-bl'OmO-llB-Cl'llO1O-170t,2ldihydroxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole and the N- acyl-, the 21 acylate, and the N-acyl-2l-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-bromo-llB-chloro-lh-hydroxy- 20-oxo-4-pregneno-[3,2-clpyrazole and the N-acyl derivative thereof; and the 9a-bIOn'10-1lB-ChlOlTO-21-flllOIO-l7ochydroxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole and the N- acyl derivatives thereof.

The 90,11[3-dichloro-17a,2l-dihydroxy-4-pregnene 3, 20-dione and the 9a-bromo-11p-chloro-l7a,2l-dihydroxy- 4-pregnene-3,2 -dione compounds, as well as the substituted derivatives thereof (See Page 36), used as starting materials can be obtained in the following manner, starting from the corresponding 17u,2l-dihydroxy-4-pregnene-3,20-dione.

A solution of 400 mg. of 170,21-dihydroxy-4-pregnene- 3,20-dione in 2.0 ml. dimethyl formamide, 0. 8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and water is added. The precipitate formed is filtered, washed with water, dried in air and purified by chromatography on alumina and elution with benzene. Crystallization gives 17a,21-dihydroxy-4,9(11)-pregnadiene-3,20- dione.

To a solution of 100 mg. of l7a,21-dihydroxy-4,9(1l)- pregnadiene-3,20-dione in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 17a,21-dihydroxy-4,9(l1) pregnadiene-3,20- dione 21-acetate which is isolated by the addition of Water and filtration.

To a stirred, cooled (05 C.) solution of 170c,2l-dihydroxy-4,9(1l) pregnadiene-3,ZO-dione-Zl-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-chlorosuccinimide (383 mg., 1.1 equivalent) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran 1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is poured into water (400 ml.). The resulting mixture is filtered and the residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 90,1lB-di0hl0- ro-17u,2l-dihydroxy-4-pregnene-3 ,20-dione 21-acetate.

A suspension of 9u,lla-dichloro-17u,21-dihydroxy-4- pregene-3,20-dione 2l-acetate (1.0 g.) in 0.27 N methanolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then poured into water (200 ml.) and filtered. The residue is washed with water and dried, giving a crude product, which is crystallized from acetone to yield 9a,11p-dichloro-17a,21-dihydroxy-4-pregnene-3,20-dione.

To a stirred, cooled (05 C.) solution of 17a,21-dihydroxy-4,9(l1)-pregnadiene-3,20-dione 2l-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-bromoacetamide (395 mg.) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydr-ofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is precipitated with water and filtered. The residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 9a-bromo- 11B chloro-l7a,21-dihydroxy-4-pregnene-3,20-dione 21- acetate.

A suspension of 9u-bromo-11B-ch-loro-17a,21-dihydroxy-4-pregnene-3,20-dione 2l-acetate (1.0 g.) in 0.27 N methanolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then precipitated with water and filtered. The residue is washed with water and dried, giving a crude product which is recrystallized from acetone to yield 9a-bromo-1l,8-chloro- 17,21-dihydroxy-4-pregnene-3,ZO-dione.

To a solution of 100 mg. of 9a,llfi-dichloro-17a,21- dihydroxy-4-pregnene-3,20-dione compound in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried With anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 9:1,1lfi-dichloro-l7u,2l-dihydroxy-4-pregnene-3,20-dione 21-acetate which is isolated by the addition of water and filtration.

Example 6 A 5 g. sample of 9a-fluoro-11B,17a,2l-trihydroxy-l6amethyl-4-pregnene-3,20-dione is dissolved in a mixture of 235 ml. of chloroform and 150ml. of methylene chloride, cooled in an ice bath with stirring and treated with ml. of formaldehyde (37%). An equal volume (85 ml.) of cold concentrated hydrochloric acid is added from a funnel over a 5-minute interval with stirring and cooling. The mixture is stirred at room temperature for four hours. The layers are separated and the organic layer is washed free of acid by washing three times with water and then with a 5% solution of sodium bicarbonate. The organic layers are washed free of bicarbonate, dried over magnesium sulfate and taken to dryness. The gummy residue is treated with enough hot methanol on a steam bath to effect trituration, and the resulting crystalline solid is separated by filtering the mixture while hot. (The filtrate is set aside and may deposit additional product overnight.) The crude product is dried to constant weight and purified by chromatography. The product is partially dissolved in 250 ml. of hot chloroform and diluted with an equal volume of hot benzene to complete solution. After cooling, the mixture is adsorbed in g. of basic alumina and eluted with benzene and chloroform to give 17a,20,20,21- bis(methylenedioxy) 9a-fluoro-16u-methyl-11/3-hydroxy- 4-pregnene-3-one.

The 17u,20,20,21 bis(methylenedioxy)-9a-fluoro-l6umethyl-1l/S-hydroxy-4-pregnene-3- one (3.25 g.) is dissolved in 76 ml. of dry pyridine and added to a cold solution prepared by the cautious addition of 3.25 g. of chromium trioxide (in portions) to 34.7 ml. of cold pyridine. The mixture is allowed to stand at room temperature overnight. The mixture is poured into Water and extracted three times with ethyl acetate, avoiding excessive shaking especially during the third extraction. The combined ethyl acetate extracts are washed three times with l N sulfuric acid and then with water until neutral. The combined ethyl acetate extracts are dried over magnesium sulfate and taken to dryness to give 2.94 g. of product. The product is dissolved in benzene, adsorbed on basic alumina and eluted with 8:2 benzene; chloroform to give 17a,20,

31 20,21 bis(methylenedioxy) 90c fluoro 16u-rnethyl-4- pregnene-3,11-dione.

A 2.60 g. sample of 17a,20,20,21-bis(methylenedioxy)- 9a-fluoro-16a-methyl-4-pregnene-3,1l-dione is dissolved in 95 ml. of dry benzene using dry equipment and treated with 2.43 ml. of freshly distilled ethyl formate. About 1.19 g. of a dispersion of sodium hydride in mineral oil (about 51%) is added, followed by about 1.19 g. of freshly prepared dry sodium methoxide (dried at about 175 C. oil pump for 4 hours). The air in the system is again replaced with nitrogen and the mixture, which turns yellow at once, is stirred at room temperature for one and one-half hours. At this point the color of the reaction mixture is a dark orange. The mixture is chilled in an ice bath and a cold, saturated solution of sodium dihydrogen phosphate is added gradually to decompose excess sodium hydride and neutralize the sodium methoxide. Ether is added and the layers are separated. The aqueous layers are back-extracted with ether and the combined organic layers are washed free of acid with water and then extracted three to four times with a 5% aqueous solution of sodium bicarbonate. These extracts are set aside. The product is now extracted four to five times with a cold 2% aqueous solution of sodium hydroxide. (In order to avoid emulsification, the aqueous alkali is gently poured into the separatory funnel and the layers are separated without shaking the funnel. The last two extracts may be shaken with care.) The dark liquor is back-extracted two times with ether, and finally acidified in the cold with saturated aqueous solution of sodium dihydrogen phosphate. The neutral ether-benzene fraction should be set aside and processed as described below. The product is extracted into ether, and the ether extracts are washed free of acid with a saturated solution of sodium chloride. After drying over magnesium sulfate, the ether solution is taken to dryness and the amorphous product is crystallized from methanol to give 17a,20,20,21 bis(methylenedioxy)-9afluoro 2-hydroxy-methylene-16a-rnethyl-4-pregnene-3,11- dione. This material is satisfactory for use in the next step.

A 1.00 g. aliquot of 17a,20,20,21-bis(methylenedioxy)- 91x fluoro 2 hydroxymethylene 16a methyl 4- pregnene-3,11-dione is suspended in 44 ml. of absolute ethanol and treated with 0.38 ml. of hydrazine hydrate (99100%). The air in the system is replaced with nitrogen and the mixture is quickly brought to the reflux temperature. After refluxing for one hour, the mixture is taken to dryness; the residual oil is treated with water and the resulting amorphous solid is removed by filtration, washed thoroughly With water and dried. The yield is about 900 mg. The crude product is dissolved in absolute ethanol and concentrated in vacuo until the solid separates. The solid is redissolved by heating, and then allowed to crystallize slowly to afford 17a,20,20,21-bi$- (methylenedioxy) 90c fluoro 164x methyl 11 oxo- 4-pregneno- [3 ,2-c]pyrazole.

A 455 mg. aliquot of 17a,20,20,21-bis(methylenedioxy) 90c fluoro 16a methyl 11 oxo 4 pregneno- [3,2-c]pyrazole is suspended in 75 ml. of a solution of sodium borohydride in isopropanol which is prepared by suspending an excess of sodium borohydride in isopropanol, stirring vigorously for about minutes, and filtering to separate the excess of sodium borohydride. To the suspension is added a 0.816 ml. aliquot of a solution of 0.55 ml. of triethylamine in 1.45 ml. of isoprop-anol. The mixture is stirred, and enough methylene chloride (about 30 ml.) is added, with cooling, to make the system homogeneous. One drop of water (ca ml.) is added and the mixture is stirred in a nitrogen atmosphere at room temperature overnight. Insolubles generally separate out in the course of the reaction. The mixture is then cooled, and the excess of sodium borohydride is decomposed by the addition of cold 2.5 N hydrochloric acid. The mixture (pH ca 5) is taken to dryness in vacuo and the residue is washed with water and dried to give 17oc,20,

32. 20,21 bis(methylenedioxy) 9a fluoro 11/3 hydroxy- 16a-methyl-4-pregneno-[3,2-c]pyrazole.

To a solution of 100 mg. of 17a,20,20,21-bis(methylenedioxy) 9oz fluoro 11,8 hydroxy 16a methyl- 4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate is then distilled at about 40 C. in vacuo to afford the N-acetyll7oc,20,20,21 bis(methylenedioxy) c fluoro 11B- hydroxy 16o: methyl 4 pregneno [3,2 c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 17a,20,20,21 bis(methylenedioxy)- 90c fluoro 11,8 hydroxy 16cc methyl 4 pregneno- [3,2-c]pyrazole (25 mg.) is heated on a steam bath With 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-acetyl-9a-fiuoro-1lfl,17a,21-trihydroxy-16amethyl-ZO-oxo-4-pregneno-[3,2-c]pyrazole and N-acetyl- 9oz fiuoro 21 formyloxy 115,170: dihydroxy 16amethyl-Z0-oxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9a-fluoro- 1118,17u 21 trihydroxy 16a methyl 20 oxo 4- pregneno-[3,2-c]pyrazole.

To a solution of mg. of N-acetyl-9a-fiuoro-1lfi, t,21 trihydroxy 16a methyl 20 oxo 4 pregneno- [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N acetyl 9oz fluoro 11/8,17a,21 trihydroxy 16amethyl 20 oxo 4 pregneno [3,2 c]pyrazole 21- acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl 90c fluoro 1lfi,17oc,21 trihydroxy 16amethyl 20 oxo 4 pregneno [3,2 c]pyrazole 21- acylate.

In accordance with the above procedure, but starting with the 9u-fluoro-11B,17u,21-trihydroxy-16a-methyl-20- oxo-4-pregnen-o-[3,2-c]pyrazole and using two milli-equivalents of another acylating agent, there is obtained the corresponding N-acyl-21-acylate thereof.

A, solution of 5.73 g. of N-acyI-9a-fiuoro-11;3,17a,21-

trihydroxy 16cc methyl-20-oxo-4-pregneno-[3,2-c]-pyraz-ole 2l-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product aifords 9a-fluoro-l1[i,l7 x,21-trihydroxy- 16a-methyl-20-oxo-4-pregneno-[3,2-c] pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-9a-fiuoro-l15,17a, 21 trihydroxy 16u-methyl-20-oxo-4-pregneno-[3,2-c]- pyrazole in 0.5 ml. of pyridine, cooled to C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-9ot-fluoro-115,1711, 21 trihydroxy 16a methyl-20-oxo-4-pregnene-20-one- 21-mesylate.

To 180 mg. of N acetyl 9a-fiuoro-11B,17a,21-trihydroxy-l6tx-methyl-20-oxo-4-pregneno-[3,'2-c]pyrazole 21- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-9a-fiuoro-1MAM-dihydroxy- 21-iodo-16a-methyl-20-oxo-4-pregneno-[3,2-c1pyrazole.

The N acetyl 9ot-fiuoro-11,8,17ot-dihydroxy-21-iodo- 16a methyl 20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N acetyl 9a-fluoro-115,17ot-dihydr0xy-16a-methyl-20- oxo-4-pregneno- [3,2-c] pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant Weight to give 9u-fll1010- 116,170 dihydroxy 160C methyl 20-oxo-4-pregneno- [3 ,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-9a-fluoro-l15,17a, 21 trihydroxy 16cc methyl-20-oxo-4-pregneno-[3,2-c] pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyl-formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N acetyl 17a,21 epoxy 9a-fluoro-11fl-hydroxy-16amethyl 20 oxo 4 pregneno-[3,2-c]pyrazole and N- acetyl 9:1,21 difluoro-l1,8,17a-dihydroxy-16ot-methyl- 20-oxo-4-pregneno-[3,2-c1pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filter-ed and dried to constant Weight to give 9a,21-di- 34 fluoro 17u,21-dihydroxy-16a-methyl-20-oxo-4-pregneno- [3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 9a-fiuoro-1 1 ,8,17,21-trihydroxy-16-methylene-4- pregnene-3,20-dione in place of the 9-fluoro-llfi,17u,21- trihydroxy-16ot-methyl-4-pregnene-3,20-dione, there are obtained as products the corresponding 9ot-fiuoro-11fi, 1706,21 trihydroxy 16-methylene-11,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 91xfluoro 17o,2l dihydroxy 16-methylene-11,20-dioxo- 4-pregneno-[3,2-c1pyrazole and the N-acyl derivative thereof, and the 904,21 difiuoro 11,8,17a-dihydroxy-16- methylene 11,20 dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9u,21-difluoro- 1711,21 dihydroxy 16a methyl 20 oxo4-pregneno- [3,2-C1PYrazole.

Example 7 About 6 g. of 17ot,20,20,21-bis(methylenedioxy)-l1B- hydroxy-l6u-methyl-4-pregnene-3-one (Example 4) is suspended in about 35 ml. of dry benzene, and to this suspension is added 6 ml. of ethyl formate and about 1 g. of freshly prepared sodium methoxide. The mixture is allowed to stand at room temperature under nitrogen for 1% hours and is then cooled in an ice bath. The mixture is then acidified with an excess of a saturated aqueous solution of potassium dihydrogen phosphate. Ether is added and the product is extracted several times with a 2% aqueous solution of sodium hydroxide. The extracts are back-extracted with ether which is acidified with cold 2.5 N HCl, and then extracted with methylene chloride. The methylene chloride extracts are washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate and then taken to dryness. The resulting product is crystallized with ether; petroleum ether to give c,20,- 20,21 bis(methylenedioxy) -11/i-formyloxy-2-hydroxymethylene-l6ot-methyl-4-pregnene-3-one.

To 1.422 g. of l7oc,20,20,21-bis(methylenedioxy)-11B- formyloxy 2-hydroxymethylene-16u-methyl-4-pregnene- 3-one, suspended in 18 ml. of absolute ethanol, is added 0.45 ml. of phenylhydrazine. The reaction mixture is refiuxed for 40 minutes under nitrogen and then cooled. The 17OL,20,20,21 bis(methylenedioxy) llfi-formyloxy- 16oz methyl-2-phenyl-4-pregneno-[3,2-c]pyrazole, which is formed as the major product, separates out and is recrystallized.

The 17u,20,20,21-bis(methylenedioxy)-1lp-formyloxy- 16a methyl 2'-phenyl-4-pregneno-[3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of 11B,17a,2l-trihydroxy-16a-methyl-ZO-oxo-2'-phenyl-4- pregneno-[3,2-c]-pyrazole and 11 B,17u,21-trihydroxy-16oamethyl 20-oxo-2-phenyl-4-pregneno-[3,2-c]pyrazole 21- formate.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and 35 dried to constant weight to give 11p,17a,21-trihydroxy- 16m-rnethyl-20-oxo-2-phenyl-4-pregneno- [3 ,2-c] pyrazole.

Example 8 To a solution of 0.5 millimole of 17a,20,20,21-bis (methylenedioxy) 11/3 hydroxy 2-hydroxymethylene- 16a-methyl-4-pregnene-3-one (Example -4) in about 3 ml. of absOlute ethanol is added 0.6 millimole of sodium acetate and then 0.6 millimole of methylhydrazine sulfate. The mixture is refluxed under nitrogen for 40 minutes and then filtered hot. The filtrate is taken to dryness, Water is added, and the 17u,20,20,21-bis(methylenedioxy) N,16e-dimethyl-11,8-hydroxy-4-pregneno-[3,2-c] pyrazole Which is formed as the major component is removed by filtration.

Alternately, a mixture of 1',16a-dimethyl-, and 2',16adimethyl 17a,20,20,21 bis(methylenedioxy) 11p hydroxy-4-pregneno-[3,2-c]pyrazole is prepared by heating 17oc,20,20,21 bis(methylenedioxy) 11B hydroxy 2- methoxymethylene 16a methyl 4 pregnene-B-one, with methanol in the presence of p-toluenesulfonic acid to form the 17u,20,20,2l-bis(methylenedioxy)-1lfi-hydroxy-2-methoxymethylene-16a-methyl-4-pregnene-3 one, and then reacting the latter compound with methylhydrazine, following the detailed procedures given in column 38, but using methylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

In accordance with all the above procedures, but using other alkyl substituted hydrazines such as ethyl-, fl-hydroxyethyl-, propyl-, butylhydrazines, and the like, in place of methylhydrazine, there are obtained the corre sponding 1'-alkyland 2'-alkyl-l7u,20,20,21-bis(methylenedioxy) 11,8 hydroxy-16a-methyl-4-pregneno-[3,2-c] pyrazoles.

The 17a,20,20,21 bis(methylenedioxy) N,16a dimethyl-11/3-hydroxy-4-pregneno-[3,2-c] pyrazoles may be prepared by the following procedure:

The 17a,20,20,21 bis(methylenedioxy) Ilfl hydroxy 2 hydroxymethylene-l6m-methyl-4-pregnene-3- one is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is Washed three times with cold Water and the resulting amorphous solid is dried at 80 C. for one hour in high vacuum to give 17cc,20,20,21-bi$ (methylenedioxy)- 1 l fi-hyd roxy- 1 6a-methyl-4-pregneno- 3,2-c] pyrazole.

A solution of about 0.47 millimole of 17a,Z0,20,21-bi$ (methylenedioxy) 1lfl-hydroxy-l6a-methyl-4-pregneno- [3,2-c]pyrazole in 10 m1. of benzene is treated with about 30-38 mg. of about 51% sodium hydride (in oil suspension). After the addition of 2-3 ml. of dimethylformamide (dried over calcium hydride) and 5 ml. of methyl iodide, the mixture is stirred at room temperature overnight. The product is filtered, washed with methylene chloride, and the filtrate and washings are taken to dryness. The residue is treated with water and the product is filtered to afford as a major component the 17zx,20,20, 21 bis(methylenedioxy) 11B hydroxy N,l6a dimethyl-4-pregneno- 3 ,2-c] pyrazole.

In accordance with the above procedure, but using another alkylating agent, for example, ethyl iodide, propyl iodide and the like, in place of the methyl iodide, there is obtained the corresponding N alkyl 17a,20,20,21 bis- (methylenedioxy) 11B hydroxy 16a methyl 4- pregneno [3,2-c] pyrazole.

The 17a,20,20,21-bis (methylenedioxy) -1'1,B-hydroxy-2'- 16ot-dimethyl-4-pregneno-[3,2-c]pyrazole mg.) is heated on a steam bath with 1 ml. of 60% formic acid for about 20 minutes and then filtered hot. The filtrate is taken to dryness, Water is added, and a mixture of the 115,170: 21 trihydroxy 2',16a-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole and its 21-formate is recovered by filtration. A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 11fi,17oc,21 trihydroxy 2,16a-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole.

To a solution of mg. of 11fi,17a,21-trihydroxy-2'- 16e-dimethyI-ZO-oxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The 11 S,l7a,2l-trihydroxy-2',l6u-dimethyl-20- oxo-4-pregneno-[3,2-c]pyrazole 21-acetate is then isolated by addition of Water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding llfi, :,21 trihydroxy 2,16a-dimethyl-20-oxo-4-pregneno- [3,2-c]pyrazole 21-acylate.

To a solution of 85 mg. of 11B,17a,2l-trihydroxy-2',16adimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give 11/3,17oc,21 trihydroxy 2',16a-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate.

To mg. of 11p,17u,21-trihydroxy-2',16a-dimethyl- 20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give 11p,17a-dihydroxy- 211 iodo-Z,1Got-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole.

The 11p,17a-dihydroxy-21-iodo-2',16a-dimethy1-20-oxo- 4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with Water, and the material which separates is recovered by filtration. The product is Washed with water, dried and recrystallized from ethyl acetate to give 11p,17a-dihydroxy-2,16a-dimethyl-20-oxo-4-pregneno- 3 ,2-c] pyrazole.

To a solution of 62 mg. of 11fi,17e,21-trihydroxy-2, 16a-dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 17a,21-epoxy-1lfi-hydroxy- 2,16a-dimethyl-ZO-oxo-4-pregneno-[3,2,-c]pyrazole and 21 fluoro 11p,17a-dihydroxy-2',16a-dimethyl-20-oxo-4- pregneno-[3,2-c]-pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2'-methyl l7o,20,20,21-bis(methylenedioxy) 1lfl-hydroxy-4-pregneno-[3,2-c] pyrazole, but using the 1'-methylderivative in place of the 2-methyl-derivative, there are obtained the corresponding 1-methyl compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,2l-bis(methylenedioxy)-2-hydroxymethylene-4-pregnenoderivative which is obtained from each of the starting materials which are listed in columns 2, 3, and 4, there are obtained the corresponding l-methyl and 2-methyl derivatives.

Example 9 To 200 mg. of 17a,20,20,2 l-bis(methylenedioxy)-115- hydroxy 2-hydroxymethylene-16a-methyl-4-pregnene-3- one (Example 4) in 7 cc. of absolute ethanol is added 82 mg. of sodium acetate and then 102 g. of cyclohexylhydrazine oxalate. The mixture is refluxed under nitrogen for one hour. The insolubles are removed by filtration. The filtrate is taken to dryness. The residue is dissolved in 3 cc. of ether and the ether solution is washed successively with 2% aqueous sodium hydroxide and then with water to neutrality. The ether solution is then dried over magnesium sulfate, filtered and taken to dryness to give a residue which has as the major component the N-cy-clohexyl 17ot,20,20,2l bis-(methylenedioxy)-l1B-hydroxyl6a-methyl-4-pregneno- [3 ,2-c] -pyrazole.

Alternately, a mixture of l-cyclohexyland the 2-cyclohexyl 17a,20,20,21 bis(methylenedioxy)-11[3-hydroxy-4-pregneno-[3,2-c]pyrazole is prepared by heating 17Ot,20,20,21 bisQmethylenedioxy) l lfi-hydroxy-2-hydroxymethylene-16a-methyl-4-pregnene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17a,20,20,21 bis(methylenedioxy) 11B hydroxy-2- methoxymethylene 16oz methyl-4-pregnene-3-one, and then reacting the latter compound with cyclohexylhydrazine following the detailed procedures given in column 38, but using cyclohexylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

A 150 mg. aliquot of the N-cyclohexyl-l7u,2=0,20,21- bis(methylenedioxy) 11B hydroxy-16u-methyl-4-pregneno-[3,2-c]-pyrazole is heated under nitrogen with cc. of a 60% aqueous solution of formic acid for about 40 minutes. The mixture is taken to dryness and water is then added. The product is extracted with chloroform, and the chloroform solution is washed with saturated aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution and then with water. The chloroform solution is dried over magnesium sulfate, and then taken to dryness to give a residue. This is taken up in ether containing a little methanol, stirred with 75 mg. of Darco G-60 (a decolorizing charcoal), filtered and taken to dryness to give N-cyclohexyl-l1fl,17ot,2l-trihydroxyl60t-methyl-20-oxo-4-pregneno- 3,2-c] py-razole.

The 2 cyclohexyl-l15,17a,2l-trihydroxy-l6ot-methyl- 20-oxo-4-pregneno-[3,2-c]pyrazole is converted into the 2l-acetate, the 2-cyclohexyl-115,17ot-dihydroxy-l6a-meth yl-20-oxo-4-pregneno-[3,2-c1pyrazole, and into the 2-cyclohexyl 21 fluoro-l1,8,17ot-dihydroxy-16a-methyl-20- oxo-4-pregneno-[3,2-c]pyrazole, following the detailed procedures given in Example 8 for the corresponding 2- methyl-derivatives.

In accordance with the above procedures beginning with the 2'-cyclohexyl-17a,20,20,2l-bisQmethylenedioxy)- 11,8 hydroxy 16otmethyl-4-pregneno-[3,2-c1pyrazo1e, but using the 1-cyclohexyl-deriv-ative in place of the 2'- cyclohexyl-derivative, there are obtained the corresponding 1'-cyclohexyl-compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,2l-bis(methylenedioxy)-2-hydroxymethylene-4-pregnene-derivative which is obtained from each of the starting materials which are listed in columns 2, 3, and 4, there are obtained the corresponding 1'-cyclohexyland 2-cyclohexyl-derivatives.

38 In accordance with the above procedures, but using other cycloalkylhydrazines in place of cyclohexylhydrazine there are obtained the corresponding 1- and 2-cycloalkyl derivatives.

Example 10 A mixture of mg. of l7u,20,20,2l-bis(methylenedioxy) 11B hydroxy-Z-hydroxymethylene-16a-methyl-4- pregnene-3-one and 0.028 ml. of phenylhydrazine are refluxed under nitrogen in 1.2 ml. of absolute ethanol for 50 minutes. The reaction mixture is taken to dryness. Water is added and the product is filtered to give an amorphous solid, which is washed successively with water, dilute acid, water, and petroleum ether. The product is crystallized from methanol to give l7a,20,20,2l-bis (methylenedioxy) 11B hydroxy-16a-methyl-2-phenyl- 4-pregneno- 3 ,2-c] pyrazole.

Alternately, a mixture of the 1-phenyland 2'-phenyl- 17a,20,20,21 bisQmethylenedioxy) llfi-hydroxy-l6umethyl-4-pregneno-[3,2-c1pyrazole is prepared by the following route: A mixture of 1 gram of '17ot,20,20,21-bl5- (methylenedioxy) 11/3 hydroxy-2-hydroxymethylene- 16a-methyl-4-pregnene-3-one, 200 ml. of methanol, and 200 mg. of p-toluenesulfonic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed two times with 2 N aqueous sodium hydroxide solution and then with water. The ethyl acetate extract is then dried and concentrated in vacuo. The 17o,20,20,21 bis(methylenedioxy) hydroxy-2- methyoxymethylene a methyl-4-pregnene-3-one is obtained by direct crystallization or by chromatography on acid-washed alumina and elution with etherzchloroform mixtures.

A mixture of 500 mg. of (17tx,20,2(),2l-bis(methylenedioxy) 11/3 hydroxy-Z-methyoxymethYlene-16u-methyl- 4-pregnene-3-one), 100 ml. of ethanol, and 1 ml. of phenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogen at room temperature overnight. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The reaction mixture is then diluted with ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, concentrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benzene and ethyl acetate affords the 20,20,21 bis( methylenedioxy) 11fi-hydroxy-16ot-methyl-l '-.phenyl-4-pregneno- [3 ,2-c]pyrazole. Further elution with a mixture of 1:1 etherzpetroleum ether and crystallization from benzene, affords the 17oc,20,20,21-bi$(fl1thylenedioxy) 115 hydroxy-16a-methyl-2'-phenyl-4-pregneno- 3 ,2-c] pyrazole.

A 30 mg. aliquot of 17a,20,20,2l-bis(methylenedioxy) 11;? hydroxy 16a methyl 2-phenyl-4-pregneno- [3,2-c]pyrazole is heated on a steam bath with 2 ml. of 60% formic acid for 35 minutes. The solvents are removed in vacuo, water is added and the product is filtered off to give a mixture of 11B,17a,2l-trihydroxy-l6ot-methyl 2O oxo-2'-phenyl-4-pregneno[3,2-c]pyrazole and its 2'l-formate. The presence of formate is indicated by infrared absorption at 5.81 and 8.5 1..

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for 10 minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 1lB,17a,2l-trihydroxy 16oz. methyl-ZO-oxo-2-phenyl-4-pregneno-[3,2-c1- pyrazole.

The 11,8,17a,21 trihydroxy 16o: methyl 20 oxo-2'- 39 phenyl-4-pregnano-[3,2-c]pyrazole is treated with a mixture of 1.5 ml. of pyridine and 1.5 ml. of acetic anhydride and the mixture is allowed to stand at room temperature overnight. The solvents are removed in vacuo, water is added and the 11/3,l7a,21-trihydroxy-16a-methyl-20-oxo- 2'-phenyl-4-pregneno-[3,2-c]pyrazole 2l-acetate is removed by filtration. After drying, the compound is dissolved in methylene chloride, a few drops of 2.5 N HCl are added and the mixture is taken to dryness. The resulting 1l/3,l7oc,21 trihydroxy 16a methyl-20-oxo-2- phenyl-4-pregneno-[3,2-clpyrazole 21-acetate hydrochloride salt is soluble in methylene chloride and can be crystallized from acetone.

The 11 B,17a,2l-trihydroxy-16tx-methyl-20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole (100 mg.) is dissolved in 1.2 cc. of dimethylformamide. The solution is cooled to C. and 0.07 cc. of methane sulfonyl chloride is added. The mixture is kept at 0 C. for about ane hour, 3 cc. of water is added and the product is extracted into 100 cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness to afford the 11/3, 17cc, 21- trihydroxy 60:,16a dimethyl 20-oxo 2'-phenyl-4-pregneno-[3,2-c]pyrazole 21-mesylate.

The 11B,17tx,21 trihydroxy 16cc methyl 20 oxo-2'- phenyl-4-pregneno-[3,2-c]pyrazole 21-mesylate is suspended in 5.5 cc. of acetone and 117 mg. of sodium iodide is added. The mixture is refluxed under nitrogen for about one hour. It is then cooled on ice. On the addition of Water there is formed a white precipitate which is filtered off, washed with water, and dried under vacuum to give the 11 [3,l7ot-dihydroxy-2l-iodo-16a-methyl-20-oxo- 2-phenyl-4-pregneno- [3 ,2-c] pyrazole.

The above material is dissolved in cc. of ethanol. Five hundred mg. of sodium bisulfite in 5 cc. of water is added, and the mixture is refluxed for one hour under nitrogen. Ten cc. of water is then added and the product is extracted into 100 cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness, to give a residue which is purified by chromatography on sill-ca gel. The 11B,17u-dihydroxy-l6a-methyl-20-oxo-2'- phenyl-4-pregneno-[3,2-c]pyrazole so obtained is crystal lized from acetone-ether.

Silver dihydrogen phosphate is prepared by the reaction of 32 g. of trislver phosphate with ml. of 100% phosphoric acid with thorough mixing in a one-liter 3- necked round-bottomed flask. The silver dihydrogen phosphate is washed with two portions of diethyl ether, which are removed by decantation, to remove some of the phosphoric acid. About 200 ml. of acetonitrile are added to cover the silver dihydrogen phosphate, and the mixture is heated to reflux temperature. At this point g. of l1,6,17a-dihydroxy-2l-iodo-l6at-methyl-20-oxo-2'- phenyl-4-pregneno-[3,2-c]pyrazole is added and the mixture is refluxed in a nitrogen atmosphere with stirring for 75 minutes. The reaction mixture is then cooled over a period of about one hour to room temperature. Then 200 g. of ice Water are added, and the acetonitrile is removed in vacuo at a temperature below C. The pH of the resulting aqueous suspension is adjusted to 6.4 by the addition of 23 ml. of saturated aqueous sodium carbonate solution. A precipitate is formed and separated by filtration. The precipitate is washed with water until no untraviolet absorbing material is detected in the wash water. The filtrate and wash water are combined and freeze dried to separate a solid material from the water. The solid material is triturated with a total of 770 ml. of methanol in seven portions. The methanol-insoluble material is separated by filtration. The filtrate is then concentrated in vacuo to 200 ml. and passed through a column containing 60 g. of a cation exchange resin (IR- 120) in its hydrogen form. The column is washed with methanol until the washings contain no ultraviolet absorbing material. The combined eluate and washings are concentrated to a volume of 15 ml., and 150 ml. of ether are added. The precipitate which forms is recoverd by 4 0 filtration, washed with ether, and dried for about 16 hours in a desiccator, to give 11B,l7a-dihydroxy-l6a-methyl-20- oxo 2' phenyl -4 -pregneno-[3,2-c]pyrazole 21- dihydrogen phosphate.

The monoand the dialkali metal salts of the 2l-dihydrogen phosphate compound are obtained by neutralizing the 2l-dihydrogen phosphate ester with an alkali metal methoxide.

To a solution of 62 mg. of l1B,17a,2l-trihydroxy-16amethyl 20-oxo-2-phenyl 4-pregneno-[3,2-c]pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 17a,2l-epoxy-llfi-hydroxy- 16a methyl-20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole and 21 fluoro 11,8,l7a-dihydroxy-l6a-methyl-20-oxo-2- phenyl-4-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel. 1

In accordance with the above procedures beginning with the 2'-phenyl-17a,20,20,21-bis(methylenedioxy)- 11 B-hydroxyl 6a-methyl-4-pregneno- 3 ,2-c] pyrazole, but using the 1'-phenyl-derivatives in place of the 2-phenylderivatives, there are obtained the corresponding 1-phenyl-compounds.

In accordance with all of the above procedures, but starting with the 17or,20,20,21-bis(methylenedioxy)-2-hydroxymethylene-4-pregnene derivatives which is obtained from each of the starting materials which are listed in columns 2, 3, and 4, there are obtained the corresponding 1'-phenyland 2-phenyl-derivatives.

Example 11 To a mixture of 223 mg. of 17a,20,20,21-bis(methy1- enedioxy)-11B hydroxy-2-hydroxymethylene-l6a-methyl- 4-pregnene-3-one (Example 4) in 15 ml. of absolute ethanol is added 49 mg. of sodium acetate and then mg. of p-tolylhydrazine hydrochloride. The mixture is refluxed under nitrogen for 45 minutes. On cooling, a solid precipitates which is filtered. The filtrate is taken to dryness and Water is added. The product is filtered, washed with Water, dilute acid, and again with water until neutral to afford a solid which has as the major component the 17a, 20,20,21 bis(methylenedioxy)-11B-hydroxy-16u-methyl- 2-(p-tolyl)-4-pregneno-[3,2-c]pyrazole. The product is purified by dissolving 235 mg. of the crude material in 30 cc. of methanol and stirring at room temperature with 235 mg. of Nuchar C1000N (a decolorizing charcoal). The mixture is filtered and the filtrate is concentrated and then crystallized to give 17u,20,20,2l-bis(methylenedioxy)-1lfi-hydroxy-l6a-methyl-2-(p-tolyl) 4 pregneno- [3,2-c]pyrazole.

Alternately, a mixture of 1'-(p-tolyl)- and 2'-(p-tolyl)- l7a,20,20,21 bis(methylenedioxy)-11fi-hydroxy-4-pregneno-[3,2-c]pyrazole is prepared by heating 17tx,20,20,21- bis(methylenedioxy) l1B-hydroxy-2-hydroxymethylene- 16u-methyl-4-pregnene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17oc,20,20,21- bis(methylenedioxy) 1l13-hydroxy-2-methoxymethylene- 16tx-methyl-4-pregnene-3-one, and then reacting the latter compound with p-tolylhydrazine following the detailed procedures given in column 38, but using p-tolylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

A 13 mg. aliquot of the 2'-(p-to1yl)-17a,20,20,21-bis (methylenedioxy) 1lfl-hydroxy-16a-methyl-4-pregneno- [3,2-c]pyrazole is heated on a steam bath with 1 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The mixture is taken to dryness, water is added and the product is filtered off to give 11fl,17a,21-trihy- 

1. A COMPOUND SELECTED FROM THE GROUP OF COMPOUNDS HAVING STRUCTURAL FORMULAS A AND B: 